Cushing's syndrome, or hypercortisolism, is a condition that is characterized by a fatty hump between the shoulders (buffalo hump), a rounded face (moon face) and pink or purple stretch marks on the skin.

The condition is caused by long-term exposure to high levels of cortisol, a hormone that reduces inflammation (swelling) in the body. Cortisol, also referred to as hydrocortisone, is naturally produced by the adrenal glands in the body. The steroid hormone, which is an essential component of the body's endocrine system, regulates proper glucose metabolism, blood pressure and insulin release for blood sugar maintenance, and it is involved in the inflammatory response.

Excessive cortisol levels may be caused by factors outside of the body (exogenous) or factors inside the body (endogenous). The syndrome is most often caused by high doses of cortisol-like medication (corticosteroids), which are often prescribed to treat chronic inflammation. Cushing's syndrome may also develop if the adrenal glands make too much cortisol, or if the pituitary gland releases too much adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands to release cortisol. When excessive secretions of ACTH cause the condition, it is called Cushing disease. Tumors, either cancerous or benign, cause these glands to produce too many hormones.

Researchers estimate that about 13 million Americans are diagnosed with Cushing's syndrome each year. It is estimated that 10-15 out of one million people are diagnosed with Cushing's syndrome each year worldwide.

Cushing's syndrome can be fatal if left untreated. Severe symptoms may include high blood pressure, bone loss, kidney stones, infections, and sometimes, diabetes. Treatment for Cushing's disease depends on the cause. If the condition is drug-induced, patients are often advised to reduce or discontinue use of the medication. Many conditions that are treated with corticosteroids can also be treated with non-corticosteroid drugs. This allows the patient to either reduce or eliminate the use of corticosteroids altogether. If a tumor is causing the condition, treatment may include surgery and/or radiation therapy. This treatment is typically performed after a diagnosis to prevent the tumor from growing and worsening the patient's condition.

Most patients fully recover from the condition and experience complete remission of symptoms after treatment. However, in some instances, patients with Cushing's syndrome never experience a full recovery to normal adrenal gland function. In such cases, lifelong hormone replacement therapy is necessary to maintain normal levels of cortisol in the body.

Drug-induced (exogenous): The most common cause of Cushing's syndrome is the long-term use of high doses of oral corticosteroids. These drugs have the same effects on the body as cortisol, which regulates proper glucose metabolism, blood pressure and insulin release for blood sugar maintenance and inflammation. Since this form of Cushing's syndrome is caused by factors outside of the body, it is also called exogenous Cushing's syndrome. Corticosteroids that commonly cause this condition include prednisone, dexamethasone (Decadron®) and methylprednisolone (Medrol®).

Corticosteroids are often prescribed to treat inflammatory diseases such as rheumatoid arthritis, lupus (autoimmune disorder that causes chronic swelling) and asthma, or to prevent the body from rejecting a transplanted organ. Since the doses necessary to treat these conditions are usually higher than the amount of cortisol produced in the body of a healthy person, some individuals develop Cushing's syndrome.

Individuals may also develop Cushing's syndrome after they receive high-doses of intravenous corticosteroids, which are often used to treat joint pain, bursitis (inflammation of a fluid-filled sac between the joint and tendon) and back pain.

Although certain inhaled steroids (used to treat asthma) and steroid skin creams (used to treat skin conditions like eczema) are in the same category of drugs, they generally do not cause Cushing's syndrome unless they are taken in extremely high doses.

Pituitary: The pituitary gland, located at the base of the brain, secretes a hormone called adrenocorticotropic hormone (ACTH). This hormone stimulates the adrenal glands to produce cortisol. If the pituitary gland produces too much ACTH, Cushing's syndrome may result. A non-cancerous (benign) tumor in the pituitary gland causes excessive ACTH to be secreted, which subsequently stimulates the adrenal glands to produce more cortisol. When this form of the syndrome develops, it is called Cushing's disease. This form of Cushing's syndrome occurs five times more often in women than men, and it is the most common form of endogenous (caused by factors inside the body) Cushing's syndrome.

In rare cases, a tumor that grows in an organ that does not normally produce ACTH will begin to secrete high levels of this hormone, resulting in Cushing's syndrome. These tumors, which can be benign or malignant (cancerous), are most often found in the lung, thyroid, pancreas or thymus gland. This condition is called ectopic ACTH syndrome. Lung tumors cause more than 50% of these cases.

Adrenal: If the adrenal glands are not functioning properly and they secrete too much cortisol, Cushing's syndrome may result. The most common adrenal disorder that has been associated with Cushing's syndrome is a non-cancerous tumor of the adrenal cortex, called adrenal adenoma.

Cancerous tumors of the adrenal cortex are rare, but they can also cause Cushing's syndrome. Sometimes, benign tumors on one or both adrenal glands can result in Cushing's syndrome.

General: Cushing's syndrome can be difficult to diagnose because many other conditions, such as polycystic ovary syndrome (hormone disorder in women that causes enlarged ovaries), depression, eating disorders and alcoholism, share some of the same signs and symptoms. Urine, blood and saliva tests are conducted to determine if the patient has elevated levels of cortisol in the body. Patients who have excessive cortisol levels will then undergo imaging studies (body scans that produce pictures of the internal organs) to determine whether a tumor inside the body is causing the condition. If the patient is taking corticosteroids, it is suspected that the medication is causing the condition. These tests may also help the healthcare provider rule out other medical conditions with similar symptoms.

Urine and blood tests: Urine and blood tests are conducted to measure the patient's hormone levels. Cortisol is present in both the urine and blood. High levels may indicate Cushing's syndrome. For the urine test, the patient may be asked to collect a sample of urine over 24 hours. Levels higher than 50-100 micrograms a day for an adult indicate Cushing's syndrome.

Dexamethasone suppression test: The dexamethasone suppression test helps determine whether the patient has a pituitary tumor. Patients are given dexamethasone, which is a synthetic glucocorticoid (type of corticosteroid) every six hours for four days. Patients receive low doses for the first two days followed by higher doses for the last two days. Twenty-four hour urine collections are made before the drug is given and on each day of the test. Since glucocorticoids signal the pituitary gland to produce lower amounts of ACTH, the normal response after taking dexamethasone is a decline in blood and urine cortisol levels. Patients who experience no change in cortisol levels at both the low and high doses of dexamethasone may have either an adrenal tumor or ectopic ACTH-producing tumor. Patients who experience no change in cortisol levels at low doses, but normal suppression at high doses of dexamethasone, have a pituitary tumor.

The test can produce false-positive results in patients who suffer from depression, alcoholism, high estrogen levels, acute illness or stress. Also, drugs like phenytoin and phenobarbital may cause false negative results.

Corticotropin-releasing hormone (CRH) stimulation test: The corticotropin-releasing hormone (CRH) stimulation test helps distinguish between patients who have pituitary adenomas and those who have ectopic ACTH syndrome or cortisol-secreting adrenal tumors. Patients receive an injection of CRH, which causes the pituitary gland to secrete ACTH. Patients who have pituitary adenomas usually experience an increase in ACTH and cortisol levels in the blood. This response is rarely seen in patients who have ectopic ACTH syndrome and almost never observed in patients who have cortisol-secreting adrenal tumors.

Saliva test: Cortisol levels normally rise and fall throughout the day. Healthy patients experience a significant drop in cortisol levels overnight. If Cushing's syndrome is suspected, a healthcare provider may take samples of the patient's saliva from 11:00 p.m. to midnight. If cortisol levels are abnormally high, Cushing's syndrome is indicated.

Imaging studies: Imaging studies, including computerized tomography (CT) and magnetic resonance imaging (MRI) scans, are conducted at the hospital after a patient shows elevated levels of cortisol in the urine, blood or saliva. During these procedures, which are noninvasive and painless, pictures of the internal organs are taken with machines that use X-rays and magnetic waves. These tests are used to determine the cause of the syndrome if the patient is not taking corticosteroids. The imaging studies provide detailed images of the pituitary and adrenal glands. The radiologist (specialized doctor who analyzes the images) will look for abnormalities, such as tumors, which may be causing the condition.

General: Treatments for Cushing's syndrome are designed to lower the level of cortisol in the body. Treatment options vary, depending on the cause of the syndrome. Patients may be advised to reduce or discontinue corticosteroid use if the condition is drug-induced. If a tumor is causing the condition, treatment may include surgery and/or radiation therapy. Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs or supplements. In some instances, patients with Cushing's syndrome never experience a resumption of normal adrenal function, and lifelong hormone replacement therapy is necessary.

Reducing corticosteroid use: If the cause of Cushing's syndrome is long-term use of corticosteroid medications, the healthcare provider may recommend reducing the dosage of the drug over a period of time, while still managing the underlying condition (like arthritis or asthma). Many conditions that are treated with corticosteroids can also be treated with non-corticosteroid drugs. This allows the patient to either reduce or eliminate the use corticosteroids altogether.

Patients should not alter their doses of corticosteroids or stop taking them on their own. Abruptly discontinuing corticosteroids could lead to deficient cortisol levels in the body. Therefore, patients who are advised to discontinue corticosteroid use must slowly taper off treatment.

Surgery: If the cause of Cushing's syndrome is a tumor, the doctor may recommend surgery to remove it. Pituitary tumors are typically removed by a neurosurgeon, who may perform the procedure through the patient's nose. If a tumor is present in the adrenal glands, lung or pancreas, the surgeon can remove it through a standard operation or, in some cases, by using minimally invasive surgical techniques, with smaller incisions. Health risks associated with surgical removal of such tumors include increased risk of bleeding and infection.

After surgery, patients must take corticosteroids to provide the body with the correct amount of cortisol. In most cases, the patient's body will return to normal cortisol levels, and the patient can taper off the medication. However, it may take up to a year or longer for the body to begin producing normal amounts of cortisol after surgery.

Radiation therapy: If the surgeon cannot remove the entire tumor, the healthcare provider may recommend radiation therapy in combination with surgery. Radiation therapy involves using high-energy X-rays to kill cells in the tumor. Radiation therapy may also be used for patients who are not suitable candidates for surgery.

Radiation can be administered in small doses over a six-week period, or by a technique called stereotactic radiosurgery (gamma-knife radiation). Stereotactic radiosurgery is administered directly into the tumor as a single, high dose of radiation. This limits exposure to surrounding tissues, which minimizes side effects.

Side effects of radiation therapy may include red or irritated skin, mouth sores, difficulty or soreness swallowing, shortness of breath, temporary alopecia (hair loss), fatigue, flushing, macularpapular
rash (butterfly-shaped rash on the nose and cheeks), loss of appetite, weight loss, nausea, and vomiting. Most side effects gradually subside once treatment is completed.

Other medications: If surgery and radiation are unsuccessful, medical therapy may be recommended. Medications commonly used to control excessive production of cortisol include ketoconazole (Nizoral®), mitotane (Lysodren®) and metyrapone (Metopirone®). Medical therapy has also been used before surgery in patients who experience severe symptoms of Cushing's syndrome (such as bone loss and high blood pressure).

In some cases, the tumor or its treatment will cause other hormones produced by the pituitary or adrenal gland to become deficient. In such cases a healthcare provider may recommend hormone replacement medications.

If possible, patients should avoid taking high doses of corticosteroids for long periods of time. However, patients should not alter the doses of prescribed medications unless they have consulted with their healthcare providers.

Patients, especially those who are taking corticosteroids, should be aware of the symptoms of Cushing's syndrome so that an early diagnosis can be made.

If left untreated, Cushing's syndrome can be fatal. Without treatment, patients may experience bone loss, high blood pressure, kidney stones, infections and/or diabetes. This is because cortisol regulates proper glucose metabolism, blood pressure and insulin release for blood sugar maintenance, and it is involved in the inflammatory response.

The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.